HSP25 OVEREXPRESSION ATTENUATES OXIDATIVE STRESS–INDUCED APOPTOSIS: ROLES OF ERK1/2 SIGNALING AND MANGANESE SUPEROXIDE DISMUTASE

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• 作者：Lee ; Yoon-Jin ; Cho ; Hae-Nyun ; Jeoung ; Doo-Il ; Soh ; Ja-Won ; Cho ; Chul Koo ; Bae ; Sangwoo ; Chung ; Hee-Yong ; et. al.
• 关键词：HSP25 ; Resistance to apoptosis ; Oxidative stress ; PKC ; Tyrosine kinase phosphorylation ; MnSOD ; Free radicals
• 刊名：Free Radical Biology and Medicine
• 出版年：2004
• 出版时间：February 15, 2004
• 年：2004
• 卷：36
• 期：4
• 页码：429-444
• 全文大小：1.58 M

文摘

HSP25 has been shown to induce resistance to radiation and oxidative stress; however, its exact mechanisms remain unclear. In the present study, a high concentration of H₂O₂ was found to induce DNA fragmentation in L929 mouse fibroblast cells, and HSP25 overexpression attenuated this phenomenon. To elucidate the mechanisms of H₂O₂-mediated cell death, ERK1/2, p38 MAPK, and JNK1/2 phosphorylation in the cells after treatment with H₂O₂ were examined. ERK1/2 and JNK1/2 were activated by H₂O₂; ERK1/2 activation was inhibited in HSP25-overexpressed cells, while JNK1/2 was indifferent. Inhibition of ERK1/2 activation by treatment of the cells with PD98059 or dominant-negative ERK2 transfection blocked H₂O₂-induced cell death; similarly treated HSP25-overexpressed cells were not at all affected. Moreover, inhibition of JNK1/2 by dominant-negative JNK1 or JNK2 transfection did not affect H₂O₂-mediated cell death in control cells. Dominant-negative Ras or Raf transfection inhibited H₂O₂-mediated ERK1/2 activation and cell death in control cells. On the contrary, HSP25-overexpressed cells did not show any differences. Upstream pathways of H₂O₂-mediated ERK1/2 activation and cell death involved both tyrosine kinase (PDGFβ receptor and Src) and PKCδ, while in HSP25-overexpressed cells these kinases did not respond to H₂O₂ treatment. Since HSP25 overexpression reduced reactive oxygen species (ROS), increased manganese superoxide dismutase (MnSOD) gene expression, and increased enzyme activity, involvement of MnSOD in HSP25-mediated attenuation of H₂O₂-mediated ERK1/2 activation and cell death was examined. Blockage of MnSOD with antisense oligonucleotides prevented DNA fragmentation and returned the ERK1/2 activation to the control level. Indeed, when MnSOD was overexpressed in L929 cells, similar to in HSP25-overexpressed cells, DNA fragmentation and ERK1/2 activation were reduced. From the above results, we suggest for the first time that reduced oxidative damage by HSP25 was due to MnSOD-mediated downregulation of ERK1/2.